Asthma is a heterogenous syndrome in which multiple triggering factors can induce episodic and/or chronic periods of airflow obstruction that are accompanied by increases in airway responsiveness. In children, allergen exposure and viral infections are two of the most common factors capable of producing these changes and are responsible for much of the morbidity attributable to asthmatic exacerbations. A common mechanism by which both allergen exposure and viral infection could induce airway obstruction is through augmentation of cytokine production that results in upregulation of resident or inflammatory cell functions with contribute to alterations in airway physiologic responses. To define these interrelationships, we have developed a rat model of virus- induced airway dysfunction that produces an ~asthma-like syndrome~ characterized by increased airway inflammation, alterations in airway resistance and dynamic compliance (that correlate significantly with eosinophil influx), and enhanced airway responsiveness, all of which can be attenuated significantly following corticosteroid treatment. Further, we have preliminary data to indicate that, following Parainfluenza I virus infection, Brown Norway rats (high IgE antibody producers) develop increased levels of interleukin (IL)-4 during infection which precede this asthma-like syndrome. In contrast, viral inoculation of F344 rats (low IgE antibody producers results in increased levels of interferon-gamma but no chronic airway changes as seen in the BN strain. Based on the observations, we have designed a series of experiments to prove that the susceptibility to virus-induced chronic airway dysfunction is controlled at the level of cytokine response to virus infection; genetic susceptibility is characterized by high gene expression of IL-4 and IL-5 in airways, and low gene expression of Il-2 and interferon-gamma (TH2 cytokine profile predomination). The increased Il-5 production leads to enhanced eosinophil recruitment which contributes to the observed alterations in airway physiologic responses. Although other animal models of virus- induced airway dysfunction have been studied, we feel the rat model described herein provides a unique opportunity of critically analyzing these virus/allergen interrelationships; moreover, the studies complement the eosinophil and cytokine biology studies, utilizing human tissues and cells, which are proposed in the other projects in this SCOR application.